naloxone and Spinal-Cord-Diseases

The anatomy, physiology, and pharmacology of an intrinsic neural network that monitors and modulates the activity of pain-transmitting neurons is reviewed. This system can be activated by opiate administration or by electrical stimulation of discrete brainstem sites. Evidence is presented that its pain-suppressing action is mediated in part by endogenous opiatelike compounds (endorphins). This pain suppression system is organized at three levels of the neuraxis: midbrain, medulla, and spinal cord. Activation of neurons in the midbrain periaqueductal gray matter (by electrical stimulation, opiates, and possibly psychological factors) excites neurons of the rostral medulla, some of which contain serotonin. The medullary neurons, in turn, project to and specifically inhibit the firing of trigeminal and spinal pain-transmission neurons. As part of a negative feedback loop, the output of the pain transmission neurons, i.e., pain itself, is an important factor in activating the pain-suppression system. A neural model which incorporates the experimental findings is proposed, and the clinical implications of the model are discussed.

Topics: Analgesia; Animals; Biogenic Amines; Brain; Brain Stem; Cats; Electric Stimulation; Enkephalins; Humans; Models, Neurological; Naloxone; Narcotics; Neural Inhibition; Neural Pathways; Pain; Raphe Nuclei; Rats; Serotonin; Spinal Cord; Spinal Cord Diseases; Synaptic Transmission

We examined the pharmacologic characteristics of herpes simplex virus (HSV) vector-mediated expression of proenkephalin in the dorsal root ganglion in a rodent model of neuropathic pain. We found that: (i). vector-mediated enkephalin produced an antiallodynic effect that was reversed by naloxone; (ii). vector-mediated enkephalin production in animals with spinal nerve ligation prevented the induction of c-fos expression in second order sensory neurons in the dorsal horn of spinal cord; (iii). the effect of vector-mediated enkephalin enhanced the effect of morphine, reducing the ED(50) of morphine 10-fold; (iv). animals did not develop tolerance to the continued production of vector-mediated enkephalin over a period of several weeks; and, (v). vector transduction continued to provide an analgesic effect despite the induction of tolerance to morphine. This is the first demonstration of gene transfer to provide an analgesic effect in neuropathic pain. The pharmacologic analysis demonstrates that transgene-mediated expression and local release of opioid peptides produce some effects that are distinct from peptide analogues delivered pharmacologically.

Topics: Animals; Area Under Curve; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Enkephalins; Ganglia, Spinal; Genetic Vectors; Immunohistochemistry; Ligation; Male; Morphine; Naloxone; Narcotic Antagonists; Oncogene Proteins v-fos; Pain; Pain Measurement; Pain Threshold; Protein Precursors; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Simplexvirus; Spinal Cord Diseases; Time Factors; Transgenes

A technique of epidural catheterization in rabbits is described. Twelve albino rabbits received a totally implanted epidural catheter system. The system was implanted surgically, and the functioning of the system tested for a period of 3 months. X-ray examinations following epidural contrast injections showed a distribution up to Th4 following 1.5 ml and Th8-9 following 1.0 and 1.25 ml. Epidural injection of lidocaine throughout the study period proved the system to be functioning for all 3 months. Another 12 rabbits were included for the neurotoxicological examinations following epidural catheterization, without any injections (three rabbits), epidural injections of saline (four rabbits) and meptazinol (five rabbits) once a day for 14 days. Histopathological examinations showed a fibrous cocoon, at the tip of the catheter, in all rabbits. In the group of rabbits which did not receive any injections, the cocoon was slightly infiltrated with leukocytes and local depression of the spinal cord was observed in one rabbit. In the saline-injected group this infiltration was more pronounced and in one rabbit it extended into the meninges. Three rabbits showed local depression of the spinal cord and local myelopathy of the white matter in the area adjacent to the cocoon. In the group of rabbits receiving meptazinol, three out of five had local depression and myelopathy of the white matter. In this group these findings were more pronounced. In two rabbits the myelopathy extended transversely through the white matter into the grey matter of the spinal cord. The number of pathological changes in the group receiving meptazinol was significantly higher compared to the control and placebo groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Catheterization; Drug Tolerance; Female; Injections, Epidural; Lidocaine; Lumbar Vertebrae; Meptazinol; Myelitis; Naloxone; Pain; Paralysis; Placebos; Polyradiculopathy; Rabbits; Sodium Chloride; Spinal Cord; Spinal Cord Diseases

Topics: Ataxia; Brain; Brain Chemistry; Brain Diseases; Cerebrospinal Fluid; Diagnosis, Differential; Endorphins; Enkephalins; Humans; Infant; Injections, Intravenous; Intellectual Disability; Male; Morphine; Naloxone; Necrosis; Spinal Cord Diseases; Syndrome

Topics: Brain Chemistry; Brain Diseases; Cerebrospinal Fluid; Endorphins; Enkephalins; Humans; Infant; Injections, Intravenous; Male; Naloxone; Necrosis; Spinal Cord Diseases